DNA Binding Domain Mutations Predict Progression-Free Survival of Bevacizumab Therapy in Metastatic Colorectal Cancer.

(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13-0.65; = 0.005). In contrast, truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45-27.50; = 0.017). Importantly, neither mutation subtype was associated with overall response rate. In multivariate analysis, DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13-0.77; = 0.011). The other genetic factor independently associated with PFS were deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.